Process for the preparation of 6-methyl reichstein s



United States Patent 3,211,765 PROCESS FOR THE PREPARATION OF 6-METHYLREICHSTEIN S J Allan Campbell and John C. Babcock, Kalamazoo, Mich.,assignors to The Upjohn Company, Kalamazoo, Mich., a corporation ofDelaware No Drawing. Filed July 30, 1962, Ser. No. 213,123 6 Claims.(Cl. 260397.47)

---on --OH p (I) 11 HO on HO OH;

( 111,01 .11 ornoAc (|3=O (1:0

(1v) (III) on, E0 on,

$HaOH (iJHiOH IC=O (1:0 -OH l --on 1 1 (v1) f (v) 011 H0 -on,

wherein Ac is the acyl radical of an organic carboxylic acid preferablya hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms,inclusive and the 1,2-carbon .atom linkage is a single bond linkage or adouble bond linkage.

The compounds of this invention represented by Formulae III, IV, V andVI, are useful progestational, antiinflammatory, gonadotropininhibiting, ACTH-inhibiting,

and antifertility agent-s.

5 coacting compounds.

3,211,765 Patented Oct. 12, 1965 The novel compounds of this inventioncan be prepared and administered to birds and mammals, includingvaluable domestic animals, in a wide variety of oral or parenteraldosage forms singly, or in admixture with other They can be associatedwith a pharmaceutical carrier which can be a solid material, e.g.,starch, lactose, talc, calcium stearate, etc., or a liquid, e.g., water,ethanol, mixtures thereof, corn oil, etc., in which the compound isdissolved, dispersed or suspended. The solid compositions can take theform of tablets, powders, capsules, pills or the like, preferably inunit dosage forms for simple administration or precise dosages. Theliquid compositions can take the form of solutions, emulsions,suspension, syrups, or elixirs. The novel compounds can also beadministered topically in the form of ointments, creams, lotions, andthe like, with or Without coacting antibiotics, germicides or othermaterials forming advantageous compositions therewith.

The process of this invention comprises: (a) treating a compound ofFormula I with iodine in the presence of calcium oxide and calciumchloride in methanol to produce the corresponding 2l-iodo compound (II);(b) treating the 2l-iodo compound thus obtained with an alkali metalacylate to produce the corresponding 2l-acylate (III) and (c)dehydrating the Zl-acylate thus obtained with a dehydrating agent, e.g.,with thionyl chloride in the presence of pyridine or with a mineral or aLewis acid in a polar organic solvent to produce the correspondingG-dehydro compound (VI). The compounds of Formula-e III and IV can behydrolyzed to the corresponding Zl-free hydroxy compounds, (V) and (VI),respectively and these in turn can be re-esterified to produce thecorresponding 21-a-cylates (III) and (IV), respectively.

According to the process of this invention65,17a-dihydroxy-6ot-methyl-4-pregnene3,20 dione (I) or65,17a-dihydroxy-6a-methyl 1,4 pregnadiene 3,20 dione (I) is treatedwith iodine in the presence of calcium oxide and calcium chloride inmethanol to produce the corresponding 2l-iodo compound (II) which can beseparated from the reaction mixture by conventional methods, e.g.,precipitation with water and collection on a filter or centrifuge.

The 21-iodo compound thus obtained is then taken up in a suitableorganic solvent, e.g., acetone, methyl ethyl ketone, t-butanol,dimethylformamide and the like, and treated with the alkali metal saltof an organic carboxylic acid, preferably a hydrocarbon carboxylic acid,in accordance with the procedure disclosed in U.S. Patent 2,726,240,e.g., with the alkali metal salt of an acid hereinafter listed inExample 1. The 21-acylate thus obtained is recovered from the reactionmixture and purified by conventional methods as disclosed in US. Patent2,726,240, e.g., by diluting the reaction mixture with water, extractingwith a water-immiscible solvent; and recovering the product (III) fromthe organic layer by evaporation of the solvent. The product (III) canthen be further purified by conventional methods such as chromatographyand/or recrystallization.

The 21-acyloxy compounds of Formula III are then dehydrated with thionylchloride in the presence of pyridine at a temperature range of 50 to +50C. or with a mineral or a Lewis acid in a polar organic solvent, e.g.,hydrochloric acid in acetic acid, to give the corresponding 6-dehydrocompound of Formula IV, which can likewise be recovered from thereaction mixture by conventional methods, e.g., by precipitation fromwater followed by purification by recrystallization from a suitableorganic solvent, e.g., ethyl acetate, acetone-Skellysolve B hexanes,methylene chloride, acetone and the like.

The 2l-acyloxy compounds of Formulae III and IV can be hydrolyzed inaccordance with methods known in the art, e.g., the hydrolysis ofhydrocortisone acetate to hydrocortisone, to give the corresponding2l-free hydroxy compounds of Formulae V and VI, respectively.

The 21-free hydroxy compounds of Formulae V and VI thus obtained, can bere-esterified under conventional 2l-acylation conditions, for example,using the appropriate anhydride or acid halide of an organic carboxylicacid, preferably of a hydrocarbon carboxylic acid, e.g., the acidslisted in Example 1, below.

Alternatively, the A and A -compounds of Formulae III, IV, V and VI, canbe produced by 1,2-dehydrogenation of the corresponding A and Acompounds of Formulae III, IV, V and VI by fermentative or chemicaldehydrogenation. Fermentative dehydrogenation comprises the use oforganisms such as Septomyxa, Corynebacterium, Didymella, Calonectria,Alternaria, Colletotrichum, Cylindrocarpon, Ophiobolus, Fusarium,Listeria, Erysipelothrix, Mycobacterium, Trichothecium, Leptosphaeria,Curcurbitaria, Nocardia, enzymes of fungi of the family Tuberculariaceae and the like, under fermentation conditions well knownin the art, e.g., US. Patents 2,902,410 and 2,902,411. When the A and A-2l-acyla-tes of Formulae III or IV are used as the starting steroids,the 2l-ester group is generally saponified during the fermentationprocess giving the corresponding l-dehydro 21-free hydroxy compoundwhich can be reesterified in the manner previously described.

Chemical 1,2-dehydrogenation can be carried out with selenium dioxideaccording to procedures well known in the art [Meystre et al., Helv.Chim. Acta, 39, 734 (1956)].

The following examples are illustrative of the products and process ofthis invention.

Example 1.6[3,1704,21-trihydroxy-6a-methyl-4-pregnene- 3,20-dineZI-acetate (III) To a solution of 3.1 g. of 6 8,17a-dihydroxy-6a-methyl-4-pregnene-3,20-dione (I) in 200 ml. of 5% calcium chloride in methanolwas added 3.45 g. of calcium oxide followed by dropwise addition of 2.62g. of iodine in 86 ml. of a solution of calcium chloride in methanol.The iodine was added as rapidly as the iodine color disappeared. The6/3,17a-dihydroxy-6a-methyl-21 iodo 4- pregnene-3,20-dione (II) thusobtained was precipitated with water, filtered, washed with water,dissolved in methylenechloride, dried over magnesium sulfate andfiltered. The filtrate was concentrated to dryness under a stream ofnitrogen. The residual 613,l7a-dihydroxy-6a-methyl-2l-iodo-4-pregnene-3,20-dione (II) thus obtained was taken up in 50 ml.of acetone and refluxed with 8 g. of potassium acetate under nitrogenfor 8 hours. Most of the solvent was then boiled off, water was added tothe concentrate and the product extracted with methylene chloride. Theextract thus obtained was washed with water, dried over magnesiumsulfate, concentrated to about 10 ml., combined with a similar 0.36 g.run and poured onto a 150 g. Florisil column packed wet with SkellysolveB and eluted by gradient elution (400 ml. fractions) between 5 l. of 5%acetone-Skellysolve B hexanes and 5 l. of acetone-Skellsolve B hexanes.

The fractions 23-29 containing the desired product, as determined byinfrared analysis, were combined and recrystallized fromacetone-Skellysolve B hexanes to give 0.6 g. of6B,17a,21-trihydroxy-6a-methyl-4-pregnene-3,20- dione 21-acetate, M.P.S208 C. A second crop was obtained from the mother liquors andrecrystallized from ether-methylene chloride to give the same product,M.P. 210-215 C., which was combined with 100 mg. of the first crop andagain recrystallized from acetone-Skellysolve B hexanes to give 265 mg.of 6;3,17a,21-trihydroxy- 6a-methyl-4-pregnene-3,20-dione 21-acetate(III) M.P. 218-226" C.

In the same manner other 2l-acylates of 6B,17a,21-trihydroxy-6a-methyl-4-pregnene-3,20-dione (III) are prepared byreacting 6B,17a-dihydroxy-6u-methyl-2l-iodo- 4-pregnene-3,20-dione (II)with the appropriate alkali metal acylate, in place of the potassiumacetate in Example 1, including, those in which the acyl radical is thatof, for example, a lower-aliphatic acid, e.g., formic, propionic,butyric, isobutyric, valeric, isovaleric, trimcthylacetic,Z-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic,triethylacetic, heptanoic, octanoic, a-ethyl-isovaleric, a cyclic acid,e.g., cyclopropylideneacetic, a cycloaliphatic acid, e.g.,cyclopentylformic, cyclopentylacetic, p cyclopentylpropionic,cyclohexylformic, cyclohexylacetic, B-cyclohexylpropionic, an aryl oralkaryl acid, e.g., benzoic, 2, 3, or 4-methylbenzoic, 2,3-, 2,4-, 2,5-,2,6-, 3,4- and 3,5-dimethylbenzoic, ethylbenzoic,2,4,6-trimethylbenzoic, 2,4,6 triethylbenzoic, a. naphthoic, 3-methyl-u-napthoic, an aralkyl acid, e.g., phenylacetic, phenylpropionic,diphenylacetic, triphenylacetic acid, a dibasic acid (the ester of whichcan be converted, e.g., to a sodium salt), e.g., succinic acid.

Example 2 .--6 [3,1 70:,21-trihydr0xy-6a-methyl-1,4-pregnadiene-3,20-dione 21-acetate (III) To a solution of 3.0 g. of6B,l7a-dihydroxy-6a-methyl- 1,4-pregnadiene-3,20-dione (I) in about 250ml. of 5% calcium chloride in methanol is added 3.45 g. of calcium oxidefollowed by the dropwise addition of about 2.6 g. of iodine in 86 ml. ofa 10% calcium chloride in methanol solution. The iodine solution isadded as rapidly as the iodine color disappears. After all of the iodinehas been added, water is added to the reaction mixture and theprecipitate thus obtained is filtered, washed with water, dissolved inmethylene chloride, dried over anhydrous magnesium sulfate and filtered.The filtrate thus obtained is concentrated to dryness under a stream ofnitrogen to give a residue of 65,17ot-dihydroxy-6a-methyl-2l-iodo-1,4-pregnadiene-3,20-dione (II), which is then taken up in about50 ml. of acetone and refluxed with 8 g. of potassium acetate undernitrogen for about 8 hours. Most of the solvent is then removed, wateris added and the product,6,8,17a,2l-trihydroxy-6a-methyl-1,4-pregnadiene-3,20-di0ne 2l-acetate isextracted with methylene chloride. The extract is washed with water,dried over magnesium sulfate, concentrated to about 10 ml., poured intoa 150 g. column of Florisil (synthetic magnesium silicate) packed wetwith Skellysolve B hexanes and eluted by gardient elution (400 ml.fractions) between 5 l. of 5% acetone-Skellysolve B hexanes and 5 l. of15 acetone-Skellysolve B hexanes. The fractions containing the desiredproduct as determined by infrared analysis are combined andrecrystallized from acetone-Skellysolve B hexanes to give6;8,17a,2l-trihydroxy-6a-methyl-1,4-pregnadiene-3,20-dione 21-acetate(III), a light colored crystalline solid.

In the same manner other 21-acylates of6fi,17a,2l-trihydroxy-6a-methyl-1,4-pregnadiene-3,20-dione (III) areprepared by reacting 63,17a-dihydroxy-6a-methyl-2liodo-1,4-pregnadiene-3,20-dione (II) withthe appropriate alkali metal acylate in place of the potassium acetatein Example 2, including those in which the acyl radical is that of, forexample, an acid listed in Example 1, above.

Example 3 .6-methyl-1 7 (1,21 -dihydr0xy-4,6-pregnadiene-3,20-di0ne21-acetate (IV) To a solution of mg. of6B,17u,21-trihydroxy-6amethyl-4-pregnene-3,20-dione 21-acetate (III) inabout 0.5 ml. of pyridine is added 0.03 ml. of thionyl chloride withcooling in an ice-bath. After a period of about 13 minutes the reactionmixture is poured into water. The precipitate thus obtained is collectedon a filter, washed with water, dilute hydrochloric acid and again withwater and dried to give6-methyl-17a,21-dihydroxy-4,6-pregnadiene-3,20-dione 17-acetate (V), alight colored crystalline solid which can be further purified byrecrystallization from a suitable organic solvent, e.g., ethyl acetate.

Example 4.6-methyl-170;,21-dihydroxy-4,6-pregnadiene-3,20-di0ne21-acetate (IV) A solution of 80 mg. of6fi,17a,21-trihydroxy-6amethyl-4-pregnene-3,20-dione 2l-acetate (III) in1.3 ml. of acetic acid and 0.2 ml. of concentrated hydrochloric acid iskept at room temperature (approximately 25 C.) for a period of about 4hours. Water is then added and the precipitate thus obtained iscollected on a filter, washed with water, dilute hydrochloric acid andagain with water and dried to give 6-methyl-17a,2l-dihydroxy-4,6-pregnadiene-3,ZO-dione l7-acetate (V), a light colored crystallinesolid which can be further purified by recrystallization from a suitableorganic solvent, e.g., ethyl acetate.

In the same manner substituting as the starting material in Example 3 or4 other 21-acylates of 6[3,17a,21t1ihydroxy-Ga-methyl 4pregnene-3,20-dione (III), e.g., those in which the acyl radical is thatof an acid listed in Example 1, above, is productive of thecorresponding 6-methyl-l7a,2l-dihydroxy-4,6-pregnadiene 3,20 dione21-acylate (IV).

Example 5.6-methyl-17a,21-dihydr0xy-1,4,6-pregnatriene-3,20-dine 21-acetare (IV) To a solution of 80 mg, of6B,17a,21-trihydroxy-6amethyl-1,4-pregnadiene-3,20-dione 21-acetate(III) in about 0.5 ml. of pyridine is added 0.03 ml. of thionyl chloridewith cooling in an ice-bath. After a period of about 13 minutes thereaction mixture is poured into water. The precipitate thus obtained iscollected on a filter, washed with water, dilute hydrochloric acid andagain with water and dried to give 6-methyl-l7a,21-dihydroxy-l,4,6-pregnatriene-3,20-dione 21-acetate (IV), a light coloredcrystalline solid, which can be further purified by recrystallizationwith a suitable organic solvent, e.g., ethyl acetate.

Example 6.6-methyl-17a,21-dilzydroxy-1,4,6-pregnatriene-3,20-di0r'ze21acetate (I V) A solution of 80 mg. of65,l7a,21-trihydroxy-6a-methyl-l,4-pregnadiene-3,20-dione 2l-acetate(III) in 1.3 ml. of acetic acid and 0.2 ml. of concentrated hydrochloricacid is kept at room temperature (approximately 25 C.) for a period ofabout 4 hours. Water is then added and the precipitate thus obtained iscollected on a filter, washed with water, dilute hydrochloric acid andagain with water and dried to give6-methyl-17a,21-dihydroxy-1,4,6-pregnatriene-3,20-dione 21-acetate (IV),a light colored crystalline solid, which can be further purified byrecrystallization from a suitable organic solvent, e.g., ethyl acetate.

In the same manner substituting as the starting material in Examples 5or 6 other 21-acylates of 6,8,17a,21-trihydroxy-6a-methyl-l,4-pregnadiene-3,20-dione (III), e.g., those in whichthe acyl radical is that of an acid listed in Example 1, above, isproductive of the corresponding 6methyl-17a,2l-dihydroxy-l,4,6-pregnatriene-3,20-dione 21-acylate (IV).

Example 7.6,8,170:,21-trihydr0xy-6a-methyl-4-pregnene- 3,20-di0ne (V) Asolution of 0.5 g. of 6B,17a,21-trihydroxy-6a-methyl-4-pregnene-3,20-dio-ne 2l-acetate (III) in about 50 ml. of methanol waspurged with nitrogen and a solution of 0.26 g. of potassium bicarbonatein 5 ml. of water (also purged with nitrogen) was added. The solutionwas stirred for about 5 hours under nitrogen and then 0.6 ml. of aceticacid was added. Most of the solvent was removed under vacuum on therotary evaporator. Water was added and the mixture was refrigerated. Theprecipitate thus obtained, was collected, washed with water and dried,to give 0.5 g. of 618,l7a,2l-trihydroxy-6a-methyl-4-pregnene-3,20-dione, M.P. 233-243 dec. Recrystallization from methanol gave 0.3g. of 6B,17a,21-trihydroxy-6 x-methyl- 4-pregnene-3,20-dione (V), M.P.246255 dec.,

Mil 238 m e=l2,3000

Infrared analysis was agreeable with the proposed structure and only onespot was detected by papergram analysis.

Analysis.-Calcd. for C H O (376.48): C, 70.18; H, 8.57. Found: C, 70.59;H, 8.54.

In the same manner other 21-acylates of 6B,170z,21-trihydroxy-6a-methyl-4-pregnene-3,20-dione (III) can be substituted forthe 2l-acetate to give 6fl,l7a,2l-trihydroxy-6a-methyl-4-pregnene-3,ZO-dione (V).

In the same manner substituting as starting material 6,B,l7oc,2ltrihydroxy 6a methyl-1,4-pregnadiene-3,20- dione ZI-acetate (III);6-methyl-l7a,21-dihydroxy-4,6- pregnadiene-3,20-dione 21-acetate (IV);6-methyl-l7a,21- dihydroxy-l,4,6-pregnatriene-3,20-dione 21-acetate (IV)or other 21-acylates of these compounds, Example 5 is productive of thecorresponding 2l-free hydroxy compound, 65,17 0:,21trihydroxy-6u-methyl-1,4-pregnadiene- 3,20 dione (V),6-methyl-17a,21-dihydroxy-4,6-pregna diene-3,20-dione (VI) and6-methyl-17a,2l-dihydroxy-l, 4,6-pregnatriene-3,20-diode (VI),respectively.

Example 8.-6,8,17a,21-trihydr0xy-6a-methyl-4-pregnene 3,20-di0ne21-acetate (III) A solution of mg. of6,8,l7a,21-trihydroxy-6a-methyl-4-pregnene-3,20-dione (V) in 1 ml. ofpyridine and 1 ml. of acetic anhydride was maintained at roomtemperature for about 17 hours. Crushed, ice and water was added and the6B,l7a,21-trihydroxy-6a-methyl-4-pregnene-3, 20-dione 2l-acetate thusobtained was extracted with three 10 ml. portions of methylene chloride.The methylene chloride extracts were dried over anhydrous sodiumsulfate, evaporated and the residue recrystallized fromacetone-Skellysolve B hexanes to give 6B,17a,21-trihydroxy6a-methyl-4-pregnene-3,20-dione 2l-acetate (III), M.P. 230-237 0.,

A313,, 238 m e=13,250 Infrared analysis showed the product to beidentical to that obtained in Example 1. V

In the same manner, substituting 6B,l7a,2l-trihydroxy-6a-methyl-l,4-pregnadiene-3,20-dione (IV), 6-methyl,17a,21-dihydroxy4,6-pregnadiene-3,20-dione (VI) or 6-methyl 17a,2ldi'hydroxy-1,4,6-pregnatriene-3,20-dione (VI) as starting material,Example 6 is productive of 6B,l7a,21-' trihydroxy6a-methyl-l,4-pregnadiene-3,20-dione 2l-acetate (III),6-methyl-17a,21-dihydroxy-4,6-pregna-diene-3, 20-dione 2l-acetate (IV)and 6-rnethyl-17a,21-dihydroxy- 11,4,6-pregnatriene-3,20-dione21-acetate (IV), respective- Similarly, 6,8,17a,21trihydroxy-6a-methyl-4-pregnene- 3,20-dione and the other startingmaterials named in the preceding paragraph are converted, byesterification of the Zl-hydroxy group, e.g., by reaction with theappropriate acid anhydride, acid chloride or bromide, ester by esterexchange, acid in the presence of an esterification catalyst, etc., toother 2l-acylates including those wherein the acyl group is the acylradical of, for example, the acids listed in Example 1.

What we claim is:

1. The process which comprises: (a) treating a compound of the formula:

wherein the 1,2-carbon atom linkage is selected from the linkagesconsisting of a single bond linkage and a double bond linkage, withiodine in the presence of calcium oxide and calcium chloride in methanolto produce the corresponding 21-iodo compound; (b) treating the 21-iodo7 8 compound thus obtained with an alkali metal salt of an 4. Theprocess which comprises dehydrating a comorganic carboxylic acid toproduce the corresponding 21- pound of the formula: acylate of theformula:

---0H i i 1O 2 /1\ i t A v HO 0H,

wherein R is the acyl radical of an organic carboxylic HO CH1 acidcontaining from 1 to 12 carbon atoms, inclusive, and the 1,2-carbon atomlinkage is selected from the linkages wherein R is the acyl radical ofan organic carboxylic consisting of a single bond linkage and a doublebond acid containing from 1 to 12 carbon atoms, inclusive, and linkagewith a dehydrating agent selected from the group the 1,2-carbon atomlinkage is defined as above and (c) consisting of thionyl chloride inthe presence of pyridine, dehydrating the 21-acylate thus obtained witha dehydratand a Lewis acid in a polar organic solvent, to produce theing agent selected from the group consisting of thionyl corresponding6-dehydro compound of the formula:

chloride in the presence of pyridine, and a Lewis acid in a polarorganic solvent to produce the corresponding 6de hydro compound of theformula: 25 0:0

emoR ca a 1/ til,

wherein R and the 1,2-carbon atom linkage are defined as O:

CHzOR above.

5. The process which comprises: dehydrating 619,170, 21 trihydroxy-6amethyl-4-pregnene-3,20-dione 2l-acetate with thionyl chloride in thepresence of pyridine to wherein R and the 1,2-carbon atom linkage aredefined as produce 170:,21-dihydroxy-6-methyl-4,6-pregnadiene-3,20-above. dione 21-acetate.

2. The process which comprises: (a) iodinating 613, 6. The process whichcomprises: dehydrating 65,1711,l7a-dihydroxy-6a-methyl-1,4-pregnadiene-3,20-dione with21-trihydroxy-6a-methyl-1,4-pregnadiene-3,20 dione 2liodin'e in thepresence of calcium oxide and calcium chloacetate with thionyl chloridein the presence of pyridine to ride in methanol to produce 68,17a-dihydroxy-6a-methylproduce 1711,21dihydroxy-6-methyl-1,4,6-pregnatriene-2l-iodo-1,4-pregnadiene-3,20-dione; (b) acetylating the 3,20-dion'eZI-acetate. 2l-iodo compound thus obtained with potassium acetate toproduce 613,17 a,21-trihydroxy-6u-methy1-1,4'pregnadi- References Citedby the er ene-3,20-dione and (c) dehydrating the latter compound 0UNITED STATES PATENTS with thionyl chloride in the presence of pyridineto pro- 2,887,499 5/59 Carava al 260-39745 53 gifgzgg g dlhydroxyPregnamene 2,926,181 2/60 Sondheimer et al. 260397.47 2,985,563 5/61Caravajal l9551 3. The process which comprises: (a) iodinating 618,170;-

dihydroxy-6a-methyl4-pregnene-3,20-dione with iodine in 55 3062'84411/62 Ellis 2603973 the presence of calcium oxide and calcium chloridein FOREIGN PA methanol to produce 618,17wdihydroXy-6a-methyl-21- 786 01911/57 iodo-4-pregene-3,20-dione; (b) acetylating the 21-iodo GreatBntam' compound thus obtained with potassium acetate to pro- OTHER EERENCES d e 6B,171121-tril1ydr0Xy-6a-methyl-4-pregnene-3,2041% 0 Ringoldet a1., Journ. Amer. Chem. Soc." (1959), vol. one and (c) dehydratingthe latter compound with thionyl 81, pages 3712 and 3716 li d chloridein the presence of pyridine to produce 6-methyl-17a,21-dihydroxy-4,6-pregnadiene-3,20-dione ZI-acetate. LEWIS GOITS,Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,211,765 October 12, 1965 J Allan Campbell et a1.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 7, lines 26 to 39, the formula should appear as shown belowinstead of as in the patent:

column 8 lines 3 to 14, the formula should appear as shown below insteadof as in the patent:

CHZOR HO CH Signed and sealed this 18th day of October 1966.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

1. THE PROCESS WHICH COMPRISES: (A) TREATING A COMPOUND OF THE FORMULA: